Phosphine or phosphite gold complexes of thiobenzoic acid and substituted thiophenols

ABSTRACT

1. A COMPOUND OF THE FORMULA: P(-R1)3 . 1-(AU-S-Y-),2-R2-BENZENE IN WHICH: R1 IS LOWER ALKYL, LOWER ALKOXY, PHENYL OR PHENOXY WITH EACH ALKYL OR ALKOXY HAVING FROM ONE TO THREE CARBON ATOMS: Y IS CARBON-SULFUR SINGLE BOND OR C=O; R2 IS A HYDROGEN, AMINO OR COOM WHEN Y IS C=O OR AMINO OR COOM WHEN Y IS A CARBON-SULFUR SINGLE BOND; AND M IS HYDROGEN OR AN ALKALI METAL CATION.

United States Patent PHOSPHINE 0R PHOSPHITE GOLD COMPLEXES 0F THIOBENZOIC ACID AND SUBSTITUTED THIOPHENOLS Blaine M. Sutton, Hatboro, and Joseph Weinstock, Phoenixville, Pan, assignors to Smithkline Corporation, Philadelphia, Pa. N0 Drawing. Filed July 23, 1973, Ser. No. 381,832

Int. Cl. C071: 1/12 US. Cl. 260430 8 Claims ABSTRACT OF THE DISCLOSURE Phosphine or phosphite gold complexes of thiobenzoic acid and substituted thiophenols having anti-arthritic activity are prepared by reaction of an appropriate phosphine or phosphite gold(I) halide with a substituted thiobenzoic acid or a substituted thiophenol in the presence of alkali.

This invention relates to novel phosphine or phosphite gold complexes of thiobenzoic acid and substituted thiophenols which have useful pharmacological activity. More specifically, the compounds of this invention have antiarthritic activity as measured by their ability to inhibit adjuvant-induced polyarthritis in rats.

The compounds of this invention are represented by the following structural formula:

FORMULA I in which:

R is lower alkyl, lower alkoxy, phenyl or phenoxy with each alkyl or alkoxy having from one to three carbon atoms;

Y is a carbon-sulfur single bond or C=O;

R is hydrogen, amino or COOM when Y is C=O, or amino or COOM when Y is a carbon-sulfur single bond; and

M is hydrogen or an alkali metal cation.

Preferred compounds of this invention are represented by Formula I where R is lower alkyl of from one to three carbon atoms. Also preferred are those compounds of Formula I where R is hydrogen when Y is C=O.

The compounds of this invention are prepared by reaction of a substituted thiobenzoic acid or a substituted thiophenol with a phosphine or phosphite gold halide, for example triethylphosphinegold(l) chloride, in the presence of alkali such as sodium or potassium hydroxide in a solvent such as ethanol or aqueous ethanol at about 25 for one hour. When R is carboxy, the reaction mixture is acidified to liberate the free acid product. The product phosphine or phosphite gold complexes are purified by standard crystallization or chromatographic techniques.

The phosphine or phosphite gold halides employed as starting materials are prepared by reaction of a cold (10 to solution of gold(l) chloride, prepared by mixing thiodiglycol and gold acid chloride trihydrate in aqueous alcohol, with an appropriate phosphine or phosphite. Other procedures which may be applied to the preparation of these intermediates are found in J. Chem' S0c., 1828 (1937) and 1235 (1940) and Australian J. Chem., 19:547 (1966).

Some phosphine and phosphite gold complexes are known to have anti-arthritic activity, but their utility is limited by the requirement that they be administered by the parenteral route. The compounds of this invention have 3,842,107 Patented Oct. 15, 1974 the distinct advantage of being active upon oral administration.

Although the preparation of S-triethylphosphine(thiophenyl) gold is described [Australian J. Chem, 19:539 (1966)], the benzoyl derivatives and substituted phenyl derivatives are not reported. No pharmacological activity has been disclosed for compounds of this class.

The anti-arthritic activity of the compounds of this invention is measured by their ability to inhibit adjuvantinduced polyarthritis in rats. The compounds of Formula I produce marked inhibition of the development of adjuvant arthritis in rats at daily oral doses as low as about 10 mg. per kilogram of body weight. Of particular importance is the attainment of significant serum levels of gold following oral administration of these doses.

Adjuvant arthritis in rats is produced by a single injec tion of 0.75 mg. of Mycobacterium butyricum suspended in white parafin (N.F.) into a hindpaw (left footpad). The injected leg becomes inflamed and reaches a maximum volume in three to five days (primary lesion). The animals exhibit a decrease in body weight gain during this initial period. Adjuvant arthritis (secondary phase) occurs after a delay of approximately ten days and is characterized by inflammation of the non-injected sites (right hind leg), decrease in body weight gain and further increases in the volume of the injected hind leg. The compounds of Formula I administered in the doses described above beginning on the day of adjuvant injection and continuing for 17 days thereafter, exclusive of days 4, 5, 11 and 12, protect the animals against development of both primary and secondary lesions of adjuvant arthritis.

The compounds of this invention are administered in conventional dosage unit forms by incorporating an amount sufiicient to produce anti-arthritic activity, without toxic effects, with a nontoxic pharmaceutical carrier according to accepted procedures. Preferably the dosage units will contain a phosphine gold complex of Formula I or an alkali metal salt thereof when R is carboxy in an amount of from about 0.5 mg. to about 5 mg., calculated on gold content, per unit.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.

The pharmaceutical dosage unit forms described hereinabove exclude simple non-sterile solutions of the active medicament in water or in common organic solvents and exclude simple aqueous suspensions of the active medicament in the absence of a suspending agent.

The method of producing anti-arthritic activity in accordance with this invention comprises administering internally to an anmal organism a phosphine gold complex of Formula I, usually combined with a pharmaceutical carrier, in an amount sufficient to produce anti-arthritic activity without limiting side effects. The active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred. Advantageously equal doses will be administered one or two times daily with the daily dosage regimen being from about 0.5 mg. to about mg, calculated on gold content. When the method described above is carried out, anti-arthritic activity is produced with a minimum of side effects.

The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds of this invention and their incorporation into pharmaceutical compositions, and as such are not to be considered as limiting the invention set forth in the claims appended hereto. Temperatures are in degrees centigrade unless otherwise stated.

EXAMPLE 1 S-Triethylpho sphine thiobenzoyl gold A solution of 10.0 g. (0.08 mol.) of thiodiglycol in 25 ml. of ethanol was mixed with a solution of 15.76 g. (0.04 mol.) of gold acid chloride trihydrate in 75 ml. of distilled water. When the bright orange-yellow solution was almost colorless, it was cooled to below 5 and an equally cold solution of 5.0 g. (0.0425 mol.) of triethylphosphine in 25 ml. of ethanol was added dropwise to the stirred solution. After addition, the cooled mixture was stirred for 30 minutes. The solid that separated was removed by filtration and the filtrate was concentrated to about 30 ml. to yield a second crystal crop. The combined solid was washed with aqueous ethanol (2: 1) and recrystallized from ethanol by addition of water to the cloud point to give triethylphosphinegold(I) chloride as white needles, m.p. 8586.

To a solution of 0.69 g. (0.005 mol.) of thiobenzoic acid in ml. of ethanol was added 0.28 g. (0.005 mol.) of potassium hydroxide in 10 ml. of ethanol followed by 1.75 g. (0.005 mol.) of triethylphosphinegold(I) chloride in 25 ml. of ethanol. The reaction mixture was stirred for one hour at 25 under nitrogen, then it was filtered and the filtrate was evaporated to dryness. The residue was taken up in about 20 ml. of chloroform and chromatographed on 50 g. of silica gel with benzene and benzenemethanol (1:1) to give the title compound, m.p. 6870 (methanol).

EXAMPLE 2 S-Triethylphosphine (2-carboxyphenylthio) gold To a solution of 0.400 g. (0.01 mol.) of sodium hydroxide in 20 ml. of aqueous ethanol (1:1) was added 0.77 g. (0.005 mol.) of o-mercaptobenzoic acid in 20 ml. of ethanol, followed by 1.75 g. (0.005 mol.) of triethylphosphinegoldfl) chloride in 20 ml. of ethanol-chloroform (1:1). The solution was stirred at 25 under nitrogen for one hour, then it was filtered and the filtrate was acidified with 6 ml. of 1N acetic acid to about pH 5.5. The acidic solution was evaporated to dryness and the residue was dissolved in chloroform. The chloroform solution was dried (MgSO and concentrated to give the title compound, m.p. 109.5-110".

EXAMPLE 3 S-Triethylphosphine (Z-aminophenylthio gold To a cold solution of 2.52 g. (0.02 mol.) of 2-aminothiophenol in 20 ml. of ethanol was added 0.80 g. (0.02 mol.) of sodium hydroxide in 10 ml. of water followed by 7.0 g. (0.02 mol.) of triethylphosphinegold(I) chloride in 40 ml. of ethanol. A white precipitate formed immediately. The reaction mixture was stirred at 25 under nitrogen for one hour, then the precipitate was collected by filtration to give the title compound, m.p. 8788.5 (methanol).

4 EXAMPLE 4 S-Triisopropylpho sphine thiobenzoyl gold A solution of 11.82 g. (0.03 mol.) of gold acid chloride trihydrate and 7.9 g. (0.065 mol.) of thiodiglycol in 100 ml. of aqueous ethanol (3:2) was stirred until the color of auric gold disappeared. The almost colorless solution was cooled below 5 and an equally cold solution of 5.6 g. (0.035 mol.) of triisopropylphosphine in 20 ml. of ethanol was added dropwise. The volume of the final reaction mixture was increased to 250 ml. with 1:1 aqueous ethanol in order to maintain a fluid mixture. After addition, the mixture was stirred in the cold for 45 minutes. The solid was removed by filtration, washed with 1:2 alcohol-water, then dried. It was redissolved by suspension in ethanol and addition of sufficient methylene chloride for solution. The cloudy solution was filtered from a suspended gold and the filtrate was concentrated until crystallization to give triisopropylphosphinegold(I) chloride as white crystals, m.p. 184-186.

When an equivalent amount of triisopropylphosphinegold (I) chloride is substituted in the procedure of Example 1 for triethylphosphinegold(I) chloride, the title compound is obtained.

EXAMPLE 5 When an equivalent amount of triisopropylphosphinegold(I) chloride is substituted in the procedure of Example 2 for triethylphosphinegold(I) chloride, S-triisopropylphosphine(2-carboxyphenylthio) gold is obtained.

In like manner, substitution of an equivalent amount of triisopropylphosphinegold(I) chloride in the procedure of Example 3 for triethylphosphinegold(I) chloride gives S-triisopropylphosphine Z-aminophenylthio gold.

EXAMPLE 6 S-Trimethylphosphine thiobenzoyl gold A solution of 2.44 g. (0.02 mol.) of thiodiglycol in 15 ml. of methanol was mixed with a solution of 3.98 g. (0.01 mol.) of gold acid chloride trihydrate in 25 ml. of distilled water. When the orange-yellow solution became almost colorless, it was cooled to 15 and an equally cold solution of 760 mg. (0.01 mol.) of trimethylphosphine in 10 ml. of methanol was added dropwise to the stirred solution. After the addition, the cooled mixture was stirred for 30 minutes. The product was filtered off and the filtrate was concentrated in vacuo to give a second crystal crop. The combined product was washed with cold aqueous methanol (2:1) and water to give trimethylphosphinegoldfl) chloride, m.p. 228-229.

When an equivalent amount of trimethylphosphinegold (I) chloride is substituted in the procedure of Example 1 for triethylphosphinegold(I) chloride, the title compound is obtained.

EXAMPLE 7 Substitution of an equivalent amount of trimethylphosphine (I) chloride in the procedure of Example 2 for triethylphosphinegold(I) chloride gives S-trimethylphosphine- (2-carboxyphenylthio gold.

Likewise, when an equivalent amount of trimethylphosphinegold(I) chloride is substituted in the procedure of Example 3 for triethylphosphinegold(I) chloride, S- trimethylphosphine(2-aminophenylthio) gold is obtained.

EXAMPLE 8 S-Triphenylpho sphine thiobenzoyl) gold Gold acid chloride trihydrate (4.0 g.; 0.01 mol.) was reduced to aurous chloride with thiodiglycol in 1:2 aqueous ethanol. After cooling this solution in an ice bath, a cold solution of 2.62 g. (0.01 mol.) of triphenylphos phine in a minimum amount of ethanol was added with stirring. The reaction mixture was stirred for about 30 with cold aqueous alcohol and water and dried to give triphenylphosphinegoldfl) chloride, m.p. 242243.

Substitution of an equivalent amount of triphenylphosphinegoldfl) chloride in the procedure of Example 1 for triethylphosphinegoldfl) chloride gives the title compound.

EXAMPLE 9 When an equivalent amount of triphenylphosphinegold (I) chloride is substituted in the procedure of Example 2 for triethylphosphinegoldfl) chloride, S-triphenylphosphine(2-carboxyphenylthio)gold is obtained.

Similarly, when an equivalent amount of triphenylphosphinegold(I) chloride is substituted in the procedure of Example 3 for triethylphosphinegold(l) chloride, S triphenylphosphine(Z-aminophenylthio) gold is obtained.

EXAMPLE l S-Triethylphosphine 2- aminothiobenzoyl) gold When an equivalent amount of thioanthranilic acid ([15. 3,123,631) is substituted in the procedure of Example l for thiobenzoic acid, the title compound is obtained.

EXAMPLE ll When thioanthranilic acid and triisopropylphosphinegold(I) chloride are allowed to react according to the procedure of Example 1, S-triisopropylphosphine(2- aminothiobenzoyl) gold is obtained.

In like manner, S-trirnethylphosphine(2-aminothiobenzoyl)gold is obtained from thioanthranilic acid and trimethylphosphinegold(I) chloride.

Similarly, thioanthranilic acid and triphenylphosphinegold(I) chloride gives S-triphenylphosphine(Z-aminothiobenzoyl) gold.

EXAMPLE l2 S-Triethylphosphine (Z-carboxythiobenzoyl) gold Substitution of an equivalent amount of monothiophthalic acid [J. Indian Chem. Soc., 5:397 (1928)] in the procedure of Example 2 for o-mercaptobenzoic acid gives the title compound.

EXAMPLE 13 When monothiophthalic acid and triisopropylphosphinegold(I) chloride are substituted in the procedure of Example 2 for o-mercaptobenzoic acid and triethylphosphinegold(I) chloride, S-triisopropylphosphine(2 carboxythiobenzoyl)gold is obtained.

In a similar manner, S-trimethylphosphine(2-carboxythiobenzoyl)gold is prepared from monothiophthalic acid and trirnethylphosphinegold(1) chloride.

Likewise, when monothiophthalic acid and triphenylphosphinegold(I) chloride are used as starting materials, S-triphenylphosphine(Z-carboxythiobenzoyl)gold is obtained.

EXAMPLE 14 By following procedures outlined in J. Chem. Soc., 1828 (1937) trialkylphosphinegoldfl) iodide complexes are prepared, for example, triethylphosphinegoldfl) iodide.

When an equivalent amount of triethylphosphinegold (I) iodide is substituted in the procedure of Example 1' for triethylphosphinegold(I) chloride, S-triethylphosphine (thiobenzoyl) gold is obtained.

Similarly, by following procedures outlined in J. Chem. 800., 1235 (1940), trialkylphosphinegold(I) bromide complexes are prepared, for example, triethylphosphinegold(I) bromide' Substitution of an equivalent amount of triethylphosphinegold(I) bromide in the procedure of Example 1 for triethylphosphinegold(l) chloride also gives S-triethylphosphine (thiobenzoyl) gold.

By similar procedures, the other phosphine gold complexes of Formula I may be prepared as described from the appropriate phosphine gold(I) iodides and bromides.

EXAMPLE l5 S-Triethylphosphite (thiobenzoyl gold Gold acid chloride trihydrate (5.9 g., 0.015 mol.) is reduced to aurous chloride with 3.7 g. (0.03 mol.) of thiodiglycol in 1:2 aqueous ethanol. The solution is cooled to 10 and an equally cold solution of 3.72 g. (0.02 mol.) of triethylphosphite in 20 ml. of ethanol is added dropwise with stirring. The temperature is maintained at 10 and stirring is continued for 30 minutes. The ethanol is removed from the reaction mixture under reduced pressure without heating. The aqueous residue is extracted with methylene chloride and the dried extract is evaporated in vacuo. The crude product is purified by chromatography on a silica column to give triethylphosphitegold(I) chloride as an oil.

When an equivalent amount of triethylphosphitegold (I) chloride is substituted in the procedure of Example 1 for triethylphosphinegoldfl) chloride, the title compound is obtained.

EXAMPLE l6 S-Triethylphosphite(2-carboxyphenylthio)gold is prepared by substitution of an equivalent amount of triethylphosphitegold(I) chloride in the procedure of Example 2 for triethylphosphinegoldfl) chloride.

Similarly, S-triethylphosphite( 2 aminophenylthio)gold is obtained from substitution of an equivalent amount of triethylphosphitegold(I) chloride in the procedure of Example 3 for triethylphosphinegold(I) chloride.

When an equivalent amount of triethylphosphitegold (I) chloride issubstituted in the procedure of Example 10 for triethylphosphinegoldfl) chloride, S-triethylphosphite(2-aminothiobenzoyl)gold is obtained.

In like manner, substitution of an equivalent amount of triethylphosphitegold(l) chloride in the procedure of Example 12 for triethylphosphinegold(I) chloride gives S-triethylphosphite (Z-carboxythiobenzoyl) gold.

EXAMPLE 17 S-Trimethylphosphite (thiobenzoyl) gold Gold acid chloride trihydrate (4.0 g.) was reduced to aurous chloride with 2.44 g. of thiodiglycol in 1:2 aqueous methanol. The'resulting solution was cooled to below --5 and an equally cold solution of 1.5 g. of trimethylphosphite in 10 ml. of methanol was added dropwise with stirring under nitrogen. The reaction mixture was stirred for 30 minutes, filtered and the solid was washed with cold aqueous methanol and dried. The product was dissolved in 5 ml. of chloroform, diluted with 10 ml. of methanol and filtered through charcoal. The filtrate was concentrated in vacuo, cooled and diluted with ice-water to precipitate trimethylphosphitegold(I) chloride, m.p. 99-100.

Substitution of an equivalent amount of trimethylphosphitegold(l) chloride in the procedure of Example 1 for triethylphosphinegold(l) chloride gives the title compound.

EXAMPLE 18 When an equivalent amount of trimethylphosphitegold (I) chloride is substituted in the procedures of Examples 2, 3, l0 and 12 for triethylphosphinegold(1) chloride the following phosphite gold complexes are obtained, respectively:

, S-trimethylphosphite(Z-carboxyphenylthio)gold When an equivalent amount of triphenylphosphite is substituted in the procedure of Example 15 for triethylphosphite, triphenylphosphitegold(I) chloride is obtained.

7 Substitution of an equivalent amount of triphenylphosphitegold(I) chloride in the procedure of Example 1 for triethylphosphinegold(I) chloride gives the title compound.

EXAMPLE 20 When an equivalent amount of triphenylphosphitegold (I) chloride is substituted in the procedures of Example 2, 3, and 12 for triethylphosphinegold(l) chloride, the following phosphite gold complexes are obtained, respectively:

S-triphenylphosphite 2-carboxyphenylthio gold S-triphenylphosphite Z-aminophenylthio gold S-triphenylphosphite Z-aminothiobenzoyl) gold S-triphenylphosphite Z-carboxythiobenzoyl gold.

EXAMPLE 21 Ingredients: Mg./Tab1et S Triethylphosphine(2 carboxyphenylthio) gold Calcium sulfate, dihydrate 1S0 Sucrose Starch Talc Stearic acid 3 An S Y in which:

R is lower alkyl, lower alkoxy, phenyl or phenoxy with each alkyl or alkoxy having from one to three carbon atoms;

Y is a carbon-sulfur single bond or C=O;

R is hydrogen, amino or COOM when Y is C=O, or amino or COOM when Y is a carbon-sulfur single bond; and

M is hydrogen or an alkali metal cation. I

2. A compound as claimed in claim 1 where R is lower alkyl of from one to three carbon atoms.

3. A compound as claimed in claim hydrogen and Y is C=O.

4. A compound as claimed in claim 3 Where R is ethyl, said compound being S-triethylphosphine(thiobenzoyl) gold.

5. A compound as claimed in claim 2 where R is carboxy and Y is a carbon-sulfur single bond.

6. A compound as claimed in claim 5 wherein R is ethyl, said compound being S-triethylphosphine(2-carboxyphenylthio) gold.

7. A compound as claimed in claim 2 wherein R is amino and Y is a carbon-sulfur single bond.

8. A compound as claimed in claim 7 wherein R is ethyl, said compound being S-triethylphosphine(2-aminophenylthio) gold.

2 where R is References Cited UNITED STATES PATENTS OTHER REFERENCES Mann et al., Chem. Soc. 1., pp. 12351239 (1940).

Coates et a1., Aus. J. Chem. V01. 19, pp. 539-545 (1966).

Kowala et al., (1966).

Kowala et al., (1966).

-H. M. S. SNEED, Primary Examiner Aus. J. Chem. v01. 19', pp. 547- 4 Ans. J. Chem. Vol. 19, pp. 555-559 US. Cl. X.R. 424-223 32 3 I UNI-TED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. ,107 Dated October 15. 1974 Invenmfls) Blaine M. Sutton'and Joseph weglstock It is cert; lfi ed that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columfi 1, lines 30-35 and column 7', lines 38-42,

the formula reading:

q I v w (R P-AuS-Y should read 7 I h n Aus- Y f Signed and sealed this 10th day of December 1974.

(SEAL) Attest:

T- cCOY M. GIBSON JR. c. MARSHALL DANN- Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA: P(-R1)3 . 1-(AU-S-Y-),2-R2-BENZENE IN WHICH: R1 IS LOWER ALKYL, LOWER ALKOXY, PHENYL OR PHENOXY WITH EACH ALKYL OR ALKOXY HAVING FROM ONE TO THREE CARBON ATOMS: Y IS CARBON-SULFUR SINGLE BOND OR C=O; R2 IS A HYDROGEN, AMINO OR COOM WHEN Y IS C=O OR AMINO OR COOM WHEN Y IS A CARBON-SULFUR SINGLE BOND; AND M IS HYDROGEN OR AN ALKALI METAL CATION. 